Previous results of this Program Project Grant (PPG) have firmly established the important role of genome stability mechanisms in longevity and healthy aging using genetically manipulated mouse models and mouse and human cell cultures. Key publications resulting from the PPG have led to a more general acceptance of DNA repair defective mouse models of premature aging as critical tools for studying aging and developing interventions. The long-term objectives of this second renewal application are to unravel the mechanisms that underlie DNA damage-driven premature aging and its relationship with normal aging, explore potential intervention strategies and translate genome maintenance as a key factor determining health span to the human situation. Observations made during the first and second grant periods, with results from work by others, point towards two major, pro-aging end points of defects in genome stability systems: (1) Cellular responses to DNA damage, including apoptosis and cellular senescence, likely play a role in premature aging of most DNA repair defective mouse models, with stem cell compartments as a likely important target; and (2) DNA mutations and epimutations (chromatin alterations) as the irreversible consequence of errors during DNA damage processing play a key role in the age-related increase in cancer and, possibly (in the form of large genome rearrangements and chromatin alterations), also in non-cancer, degenerative aging phenotypes by causing a loss of transcriptional homeostasis. This renewal application consists of 5 research projects, an Animal and Pathology Core and an Administrative Core. A new project (Project 5) has been added to translate findings regarding genome maintenance from a pro-longevity system in mice to the human situation and will increase the PPG's significance for human aging. One core, the Array and Informatics Core, has served its function and is no longer included. For the renewal application, we now propose work in 4 main areas of research: (1) unraveling DNA damage based mechanisms of premature and normal aging using mouse models as well as mouse and human cell cultures; (2) Testing the role of genome maintenance as a pro-longevity system in humans by genetic association and functional genomics analyses; (3) Developing sets of blood-based biomarkers for premature aging in the mouse, which will be validated in normally aging mice and in a human cohort; and (4) Developing new, experimental interventions, the effects of which will be tested by using non-invasive mouse reporter models and the developed biomarker set. All five projects together with the Animal and Pathology Core will jointly work on these topics, with their research plans fully integrated, yet maintaining their own, unique spheres of interest.